Chronic pain represents a significant public health concern, affecting over 100 million adults, and accounting for over $600 billion US annually. Current treatments for chronic pain lack efficacy, and opioid treatments have led to a significant misuse, addiction, and secondary public health crisis. We have shown that endogenous pain modulation, in the form of ?placebo? manipulations have a now well-defined neural underpinning, suggestive of descending pain modulation within and perhaps from the brain to lower nervous system. Our work has identified placebo as a potentially acceptable intervention for patients with chronic pain either as a method to enhance existing treatments, or perhaps as a stand-alone treatment. To date, the contribution of spinal cord mechanisms to placebo analgesia has been largely speculative. We propose to investigate specific hypotheses about both brain and spinal cord mechanisms, and their interactions to a model of placebo analgesia through the use of functional magnetic resonance imaging (FMRI). The neural imaging of the spinal cord is an innovative new approach heretofore not feasible for the investigation of placebo mechanisms. We will combine this new approach with our previously published, and well articulated placebo manipulation and experimental design that will allow us to investigate the relative contribution of brain and cord mechanisms in placebo analgesia. We will employ both traditional fMRI, as well as functional connectivity analyses to investigate relationships among a priori regions of interest in the brain and the spinal cord. Our innovative research design, previously employed with only brain imaging, will allow for the investigation of more centrally dependent mechanisms, vs. those that are more peripheral nervous system dependent. Our team of investigators has all the necessary expertise in chronic pain, pain processing, quantitative sensory testing, neuroimaging, and experimental design to successfully accomplish the aims proposed in this application. We have repeatedly shown our ability to successfully recruit participants for the proposed design, and have successfully employed all the procedures, either in peer reviewed publications, or as demonstrated in our preliminary studies. One critical finding from our previous work has shown that the acceptability of placebo interventions is the empirical support and understanding of the mechanisms of placebo. Thus, in addition to developing a complete understanding of the mechanisms of placebo that might results in new treatment approaches, being able to describe these mechanisms to the public, pain practitioners, and to patients will increase the acceptability of them in clinical practice, thus improving pain treatment.